All mammalian cells use glucose as a major energy source; certain cell types such as neurons and blood cells being especially dependent on it. Therefore, homeostatic mechanisms are in place to maintain blood glucose levels within a narrow range, protecting the body against prolonged periods of fasting and against excessively high levels following the ingestion of a meal. These goals are met chiefly through the production of glucose by the liver and the peripheral uptake by tissues such as the skeletal muscle, fat, and the liver.
The liver can produce glucose by breaking down glycogen (glycogenolysis) and converting certain precursor molecules such as lactate, pyruvate, glycerol, and alanine, into glucose (gluconeogenesis). Glycogenolysis occurs on a more rapid time scale, beginning within two to three hours after a meal in humans, but gluconeogenesis assumes a much greater importance as the liver glycogen stores become depleted (Nordlie, R. C., and Foster, J. D. (1999) Annu. Rev. Nutr. 19:379-406; Pilkis, S. J. and Granner, D. K. (1992) Annu. Rev. Physiol. 54:885-909, and references therein). The activation of glycogenolysis is primarily mediated by glycogen phosphorylase, which is in turn regulated allosterically and by cAMP-dependent protein kinase. The rate of gluconeogenesis is controlled by the available supply of precursors, as well as the activities of the multiple enzymes in the pathway, such as phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase, and glucose-6-phosphatase. These enzymes are regulated allosterically by intracellular metabolites in some cases and also at the level of the enzyme amount by extracellular hormones. The transcriptional control of the PEPCK gene by hormones is a particularly well-studied example.
Hormones are the principal means by which the body regulates systemic carbohydrate metabolism, including the response of the liver to fasting and feeding. Following a meal, the rise in plasma glucose immediately leads to increased secretion of insulin by the pancreatic β-cells, which lowers glucose by stimulating peripheral glucose uptake and suppressing hepatic glucose production. In the fasted state, on the other hand, insulin secretion diminishes, glucagon secretion goes up, and the catecholamines and the glucocorticoids increase relative to insulin. The counterregulatory hormones such as glucagon and catecholamines enhance hepatic glucose output by stimulating both gluconeogenesis and glycogenolysis. Glucocorticoids also increase gluconeogenesis (hence their name). A careful coordination of the effects of these hormones is critical for fine-tuning the level of hepatic glucose production and is therefore a requisite part of achieving systemic normoglycemia.
Diabetes mellitus is broadly classified into type 1 (also known as insulin-dependent or IDDM) and type 2 (also known as non-insulin dependent or NIDDM) diabetes. The former is caused by an absolute deficiency of insulin, usually due to an autoimmune process affecting the β-cells of the pancreas, while the latter is caused by a combination of genetic and environmental factors that result in insulin resistance and relative insulin deficiency. Type 2 diabetes accounts for approximately 80% of the diabetic population. Other types of diabetes, such as maturity onset diabetes of the young (MODY) due to specific genetic mutations, are occasionally placed together in a third category.
The metabolic disturbances that underlie type 2 diabetes include impaired insulin secretion by pancreatic β-cells, reduced insulin-stimulated glucose uptake by skeletal muscle and adipose tissue, and increased hepatic glucose production (DeFronzo, R. A. (1997) Diabetes Rev. 5(3):177-269, and references therein). It is generally, although not universally, believed that the peripheral insulin resistance precedes the β-cell defect, as insulin resistance and compensatory hyperinsulinemia can be detected for an extended period of time well before any occurrence of glucose intolerance. Ultimately, however, the β-cells are unable to keep up, leading to a deterioration of glucose homeostasis and overt diabetes. The major site of insulin resistance depends on nutritional state. In the fasted state, the liver is the main source of hyperglycemia. In the fed or insulin-stimulated state, on the other hand, both inefficient glucose uptake by muscle and fat and impaired suppression of hepatic glucose output (HGO) contribute to postprandial hyperglycemia. While the liver can produce glucose by either glycogenolysis or gluconeogenesis, approximately 90% of the increase in HGO above baseline is attributed to accelerated gluconeogenesis (DeFronzo (1997) supra).
While type 2 diabetes is widely recognized as a polygenic disease, useful insights have been obtained from targeted gene disruptions in animals, for example, those involving the insulin receptor (IR), insulin receptor substrates (IRS), the p85 regulatory subunit of PI 3-kinase, and the Glut4 transporter. The use of the Cre/loxP system has also allowed a genetic dissection at the tissue level. A tissue-specific inactivation of the IR gene in the pancreatic β-cell (BIRKO) has been shown to produce a defect in acute phase glucose-stimulated insulin secretion, similar to that seen in type 2 diabetes (Kulkarni, R. N. et al. (1999) Cell 96:329-339). The IR deficiency in muscle (MIRKO) showed alterations of fat metabolism associated with diabetes, but unexpectedly the whole-body glucose disposal did not change significantly, suggesting that other tissues may compensate (Bruning, J. C. et al. (1998) Mol. Cell 2:559-569). On the other hand, the liver-specific IR knockout (LIRKO) generated mice with severe insulin resistance, glucose intolerance, and a failure of insulin to suppress HGO (Michael, M. D. et al. (2000) Mol. Cell 6:87-97).
Not surprisingly, oral pharmacological agents currently available for treatment of type 2 diabetes target some of these affected tissues. Sulfonylureas and repaglinide act on the β-cells to stimulate insulin secretion, and the TZDs and metformin improve insulin sensitivity in peripheral tissues such as muscle and/or liver (DeFronzo, R. A. (1999) Ann. Intern. Med. 31:281-303). However, there exists a need for additional therapeutic options which target the other major parameter of systemic glucose homeostasis, hepatic glucose output.